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Bleeding in louse-borne relapsing fever II. Fibrinolysis following treatment
782 TRANSACTIONS OF THE ROYAL SOCIETY OF TROPICAL MEDICINE AND HYGIENE. Vol. 65. No. 6. 1971.
B L E E D I N G IN L O U S E - B O R N E R E L A P S I N G F E V E R II. F I B R I N O L Y S I S F O L L O W I N G T R E A T M E N T P. L. P E R I N E , T. G A B R E K I D A N , D. A. W A R R E L L , A. D. M. B R Y C E S O N AND E. H. O. PARRY From the U.S. Naval Medical Research Unit No. 3 FieM Facility and the Department of Medicine, Haile SeUassie I University Medical School, Addis Ababa, Ethiopia
Introduction Bleeding is a c o m m o n complaint in louse-borne relapsing fever (LBRF). Severe haemorrhage is rare b u t a petechial-purpuric rash, bruising and bleeding from mucous membranes are frequent findings (BRYCESON et al., 1970). T r e a t m e n t o f the infection with tetracycline or penicillin is followed b y a Herxheimer-like reaction during which bleeding can become profuse and difficult to control. This reaction to treatment resembles that described in artificially-induced endotoxin fever (WARRELLet al., 1970) and the bleeding associated with it has many o f the features o f disseminated intravascular coagulation (PERINE et al., 1971). T h e purpose of this investigation was to determine the cause o f bleeding during the reaction to treatment in L B R F . O u r findings o f a sudden increase in fibrin-degradation products ( F D P ) following treatment was evidence for increased fibrinolysis which we attributed to disseminated intravascular clotting (DIC) in 2 patients.
P a t i e n t s and m e t h o d s Patients 7 male patients with L B R F admitted to the acute medical ward of St. Paul's Hospital, Addis Ababa, were chosen for the study. T h e diagnosis was made in each patient by finding Borrelia spirochaetes in a smear of the peripheral blood. None of the patients was bleeding at the time of admission to the study but 3 had petechial rashes (Nos. 2, 6 and 7) and 2 gave a history of epistaxis (Nos. 1 and 4). Methods Venous blood samples were obtained from an indwelling polyethylene catheter as described previously (ScHoFI~.LD et al., 1968). T h e catheter was kept patent without the use of anticoagulants. Standard methods were used to measure the WBC, platelet count, one-stage prothrombin-time, and the partial thromboplasdn time with kaolin. T h e euglobulin lysis time was measured by the method of YON KAt~LA (1958) and the fibrinogen concentration by the method of RATNOFF and IVxENZIE (1951). Serum was collected for F D P assay by adding approximately 100 units of thrombin to an aliquot of each venous blood sample and storing the serum at - 2 0 ° C . as soon as the fibrin clot was removed. T h e s e r u m samples were kept frozen until they could be assayed for F D P using the method of MERSKEY et al. (1969). This study was supported jointly by the Wellcome Trust and Work Unit, M R 005.200178, Bureau of Medicine and Surgery, Navy Department, Washington, D.C. T h e opinions and assertions contained herein are the private ones of the authors and are not to be construed as official or reflecting the views of the Navy Department or the Naval service at large. W e are deeply indebted to Dr. W. R. Pitney, Department of Haematology, Royal Postgraduate Medical School, London, who assayed the serum from this study for FDP.
P. L. PERINE~ T. GABRE KIDAN~ D. A. WARRELL~ A. D. M. BRYCESON AND E. H. O. PARRY
783
Treatment Each of the patients was given 250 mg. of intravenous tetracycline. 4 of these patients served as controls for the remaining 3 who were given heparin by continuous intravenous drip. T h e heparin was infused at a rate of 50-75 units per minute starting at least 1 hour before administration of tetracycline which was sufficient to more than triple the coagulation time prior to giving tetracycline. T h e heparin infusion was stopped after the leucocyte count had returned to pre-treatment levels. Results
T h e results of the pretreatment coagulation studies are given in the Table. It is of interest to note that the fibrinogen concentrations were elevated in each case and that the 3 patients with elevated F D P titres also had accelerated euglobulin lysis times. Both of the patients with low platelet counts also had splenic enlargement. TABLE. Pretreatment coagulation studies.
Case No. Measurement 1
2
3
4
5
6
7
Normal Range
280
210
240
180
280
90
100
200-400
Prothrombin time (sec. > control)
2
1
1
1
3
3
3
Partial thromboplastin time (sec. > control)
3
3
--
--
3
6
Euglobulin lysis time (rain. < control)
0
0
12
--
24
14
31
0-10
514
700
550
700
396
560
761
200-400
1
1
3
1
5
3
0
++
++
+
Platelets 7. 10a (per c.mm.)
Fibrinogen (mg. per 100 ml.) F D P titre log 2
Spirochaete density* + + + + + ÷
0-2
0-3
0-2
++++++
*Based on the average number of spirochaetes seen in a blood fibrin per high power field; 0-1 = + , 1-3 = + + , 3 - 6 = + + + , > 6 = + + + + . Each o f the patients demonstrated a rise in serum F D P following treatment including those who were given a heparin infusion (Fig. 1). I n 3 o f the 4 control patients the increase in serum F D P was remarkable, approaching titres produced b y normal plasma in the F D P assay. A similar increase in F D P was also seen in 1 o f the 3 patients given heparin. T h e increase in F D P started within 60 minutes following administration o f tetracycline and coincided with the onset o f rigors and the disappearance o f spirochaetes from the peripheral blood. As the b o d y temperature increased abruptly, so did the F D P titre. T h e leucocyte count began to fall and the polymorphonuclear leucocytes became vacuolated; the F D P titre reached its highest level prior to the peak in b o d y temperature and the nadir o f the leucocyte count. T h e F D P titre then decreased rather quickly to near normal levels while the leucocyte count and b o d y temperature returned slowly to baseline levels (Fig. 2).
784
BLEEDING
IN LOUSE-BORNE
RELAPSING
FEVER--II.
FIBRINOLYSIS
FOLLOWING
TREATMENT
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P. L. PERINE~ T. GABRE KIDAN~ D. A.'WARRELL, A. D. M. BRYCESON AND E. H. O. PARRY II
Tet rocycline
L I
785
4241-
"~
40-
~.
39-
L0~t
ta . ~,~
6I I I I I
__
~
3oo-
FIG. 2. Changes following tetracycline treatment in the first patient. The broken vertical line marks the disappearance of spirochaetes.
I
.~ 200.
~. ~ LO0-
I I I I
- -
~
5ooi
~ '- 400-~. ~.
t' 3oo-
01
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3
4
5
Hours
In two of the control patients (Nos. 1 and 2) the increase in serum FDP was accompartied by significant decreases (P < 0-5) in the platelet count and fibrinogen concentration. In the remaining cases the platelet count did not change significantly and the fibrinogen concentration either increased or remained stable. The increase in the fibrinogen concentration coincided with the increase in FDP titre in 2 cases (Nos. 5 and 6). There were no apparent differences between the patients treated with tetracycline and heparin and those treated with tetracycline alone. Heparin did not reduce the production of FDP prior to or following tetracycline. Nor did heparin modify the other manifestations of the Herxheimer reaction. There was no significant correlation between the severity of the Herxheimer reaction and the density of the infection or the titre of FDP. No overt bleeding occurred in any patient during the time of the study. Discussion Fibrin degradation products appear in the circulation in increased amounts as a consequence of the excessive digestion of fibrinogen or fibrin by proteolytic enzymes; their presence in serum provides incontrovertible evidence for both primary and secondary
786 BLEEDING I N LOUSE-BORNE RELAPSING F E V E R ~ I I . FIBRINOLYSIS FOLLOWING TREATMENT
fibrinolysis (MERSKEYet al., 1966). The elevated FDP titres in this study could be due to in vitro fibrinolysis, as serum for FDP assay were obtained without the addition of
fibrinolytic inhibitors. However, the accelerated pretreatment euglobulin lysis times in 4 patients are evidence of increased in vivo fibrinolytic activity. The magnitude of FDP fitre elevation following treatment also favours in vivo fibrinolysis (PITNEY, 1970, personal communication) and correlates with the clinical observation of an increased bleeding tendency following the Herxheimer reaction (BRYCESONet al., 1970). The mechanisms responsible for the activation of the fibrinolytic system are unknown. It is probable that the elevated pretreatment FDP titres, the accelerated eugiobulin lysis times and the increase of FDP following treatment are partly due to the physiological stresses resulting from the infection and its treatment. The severe rigors and pyrexia which characterize the Herxheimer reaction are well recognized activators of fibrinolysis (SHERRY et al., 1959). It is also likely that the increase in FDP following treatment is caused by the disappearance of spirochaetes from the peripheral blood. Blood sampled during the fibrile reaction in LBRF has been shown to contain endotoxin presumably of spirochaetal origin (BRYCESONet al., 1970). Endotoxin effects several changes in the blood coagulation system depending upon the animal species. It rapidly stimulates new fibrinogen synthesis (LERNERet al., 1968), impairs fibrinolysis by inhibiting the release of plasminogen activator (LIPINSKI et al., 1969), and triggers intravascular coagulation by causing the release of thromboplasfic material from platelets (HJORT and RAPAPORT,1965). The latter process is characterized by the consumption of platelets and other coagulation factors with local or secondary activation of the fibrinolytic system in response to clotting (SHERRY, 1968). The effect of endotoxin on blood coagulation is also dose related; small doses induce massive intravascular coagulation, while larger doses produce shock with minimal evidence of clotting (MARGRETTENet al., 1967). The thrombocytopenia, decreased fibrinogen concentration and elevated FDP titres following treatment in 2 of our patients are observations consistent with the initiation of DIC by release of endotoxin from dying spirochaetes. The absence of consistent changes in the platelet counts and fibrinogen concentration in the remaining cases may be explained by the varying magnitude and duration of the endotoxemia. In some, the endotoxemia stimulated fibrinogen synthesis and increased fibrinogen concentration but was inadequate to initiate significant DIC and depletion of platelets. In these cases the elevated FDP fitres probably resulted primarily from increased plasminogenic activating by stress. Less likely causes would be the release of a plasminogen activator by spirochaetes or the release of protcase enzymes from the degenerating leucocytes. The latter are capable of digesting fibrin but their lytic activity is very weak (AsTRuI" et al., 1967) and would probably not produce FDP titres of the magnitude seen in LBRF. These alternate hypotheses may explain the elevated FDP titres in the patients treated with heparin, which should prevent DIC induced by endotoxin (MARGARETTEN et al., 1967). The therapeutic implications of this study with respect to bleeding are uncertain. Heparin infusions sufficient to prolong the coagulation time beyond 60 minutes did not prevent the rise in FDP following tetracycline. An antifibrinolytic agent such as epsilon aminocaproic acid (EACA) is indicated in bleeding caused exclusively by primary fibrinolysis or by activation of the fibrinolytic system secondary to DIC in a patient in whom the dotting has stopped and the fibrinolysis has persisted (McKAY, 1968). The thrombotic complications that arise from the use of EACA in DIC should limit its use to the patient with severe bleeding, thrombocytopenia and decreased fibrinogen concentrations who does not respond to heparin therapy (McKAY, 1968). As none of our patients had severe bleeding, we would have hesitated to use EACA had it been available.
P. L. PERINE, T. GABRE KIDAN~ D. A. WARRELL, A. D. M. BRYCESONAND E. H. O. PARRY 787
Summary Treatment of louse-borne relapsing fever was followed by a sudden increase in fibrin degradation productions (FDP) in 6 of 7 patients. The FDP were believed to be the result of fibrinolysis secondary to intravascular clotting in 2 patients who also had transient decreases in plasma fibrinogen concentration and platelet count. In the remaining cases, a mixed form of fibrinolysis with elevated circulating fibrinolytic activity and local lysis secondary to intravascular clotting was presumed to be responsible for the elevated FDP. A heparin infusion in 3 patients did not prevent the increase in FDP following treatment. REFERENCES ASTRtrP, T., HENRmrISEN,J. & KW~N, H. C. (1967). Blood, 29, 134. BRYCESON, A. D. M., PARRY, E. H. O., PERINE, P. L., ~TARRELL,D. A., VUKOTICH,D. & LEITHEAD,C. S. (1970). Quart. ft. Med., 39, 129. HJORT, P. F. & RAPAPORT, S. I. (1965). Ann. rev. Med., 16, 135. LERNER, R. G., RAPAPORT, S. I., SIEMSEN, J. K. & SPITZER, J. M. (1968). Am. J. Physiol., 214, 532. LmINSKI, B., WOROWSKI, K., JELJASZEWmZ,J., NmWmROWSKI, S. & REJNI~, L. (1969). Thrornb. Diath. haemorrh., 20, 285. MARGARETrEN,W., MCKAY, D. G. & PHILLmS,L. L. (1967). Am. J. Path., 51, 61. McKAY, D. G. (1968). Proc. R. Soc. Med., 61, 40. MERSKEY, C., KLF.INER,G. J. & JOHNSON, A. J. (1966). Blood, 28, 1. --, LALEZARI,P. & JOHNSON, A. J. (1969). Proc. Soc. exp. Biol. Med., 131, 871. PERINE, P. L., PARRY, E. H. O., VUKOTICH,D., WARRELL, D. A. & BRYCESON,A. D. M. (1971) Trans. R. Soc. trop. Med. Hyg., 65, 776. RATNOFF, O. D. & MENZm, C. (1951). ft. Lab. din. Med., 37, 316. SCHOFIELD, T. P. C., TALBOT, J. M., BRYCESON, A. D. M. & PARRY, E. H. O. (1968). Lancet, 1, 58. SHERRY, S. (1968). Ann. rev. Med., 19, 247. --, LINDEMEYER,R. I., FLETCHER,A. P. & ALKJAERSlG,N. (1959). ft. din. Invest., 38, 810. VON KAULLA, K. N. & SCHULTZ, R. L. (1958). Am. J. din, Path., 29, 104. ~¢'ARRELL, D. A., POPE, H. M., PARRY, E. H. O., PERINE, P. L. & BRYCESON,A. D. M. (1970). Clin. Sci., 39, 123.
B L E E D I N G IN L O U S E - B O R N E R E L A P S I N G F E V E R II. F I B R I N O L Y S I S F O L L O W I N G T R E A T M E N T P. L. P E R I N E , T. G A B R E K I D A N , D. A. W A R R E L L , A. D. M. B R Y C E S O N AND E. H. O. PARRY From the U.S. Naval Medical Research Unit No. 3 FieM Facility and the Department of Medicine, Haile SeUassie I University Medical School, Addis Ababa, Ethiopia
Introduction Bleeding is a c o m m o n complaint in louse-borne relapsing fever (LBRF). Severe haemorrhage is rare b u t a petechial-purpuric rash, bruising and bleeding from mucous membranes are frequent findings (BRYCESON et al., 1970). T r e a t m e n t o f the infection with tetracycline or penicillin is followed b y a Herxheimer-like reaction during which bleeding can become profuse and difficult to control. This reaction to treatment resembles that described in artificially-induced endotoxin fever (WARRELLet al., 1970) and the bleeding associated with it has many o f the features o f disseminated intravascular coagulation (PERINE et al., 1971). T h e purpose of this investigation was to determine the cause o f bleeding during the reaction to treatment in L B R F . O u r findings o f a sudden increase in fibrin-degradation products ( F D P ) following treatment was evidence for increased fibrinolysis which we attributed to disseminated intravascular clotting (DIC) in 2 patients.
P a t i e n t s and m e t h o d s Patients 7 male patients with L B R F admitted to the acute medical ward of St. Paul's Hospital, Addis Ababa, were chosen for the study. T h e diagnosis was made in each patient by finding Borrelia spirochaetes in a smear of the peripheral blood. None of the patients was bleeding at the time of admission to the study but 3 had petechial rashes (Nos. 2, 6 and 7) and 2 gave a history of epistaxis (Nos. 1 and 4). Methods Venous blood samples were obtained from an indwelling polyethylene catheter as described previously (ScHoFI~.LD et al., 1968). T h e catheter was kept patent without the use of anticoagulants. Standard methods were used to measure the WBC, platelet count, one-stage prothrombin-time, and the partial thromboplasdn time with kaolin. T h e euglobulin lysis time was measured by the method of YON KAt~LA (1958) and the fibrinogen concentration by the method of RATNOFF and IVxENZIE (1951). Serum was collected for F D P assay by adding approximately 100 units of thrombin to an aliquot of each venous blood sample and storing the serum at - 2 0 ° C . as soon as the fibrin clot was removed. T h e s e r u m samples were kept frozen until they could be assayed for F D P using the method of MERSKEY et al. (1969). This study was supported jointly by the Wellcome Trust and Work Unit, M R 005.200178, Bureau of Medicine and Surgery, Navy Department, Washington, D.C. T h e opinions and assertions contained herein are the private ones of the authors and are not to be construed as official or reflecting the views of the Navy Department or the Naval service at large. W e are deeply indebted to Dr. W. R. Pitney, Department of Haematology, Royal Postgraduate Medical School, London, who assayed the serum from this study for FDP.
P. L. PERINE~ T. GABRE KIDAN~ D. A. WARRELL~ A. D. M. BRYCESON AND E. H. O. PARRY
783
Treatment Each of the patients was given 250 mg. of intravenous tetracycline. 4 of these patients served as controls for the remaining 3 who were given heparin by continuous intravenous drip. T h e heparin was infused at a rate of 50-75 units per minute starting at least 1 hour before administration of tetracycline which was sufficient to more than triple the coagulation time prior to giving tetracycline. T h e heparin infusion was stopped after the leucocyte count had returned to pre-treatment levels. Results
T h e results of the pretreatment coagulation studies are given in the Table. It is of interest to note that the fibrinogen concentrations were elevated in each case and that the 3 patients with elevated F D P titres also had accelerated euglobulin lysis times. Both of the patients with low platelet counts also had splenic enlargement. TABLE. Pretreatment coagulation studies.
Case No. Measurement 1
2
3
4
5
6
7
Normal Range
280
210
240
180
280
90
100
200-400
Prothrombin time (sec. > control)
2
1
1
1
3
3
3
Partial thromboplastin time (sec. > control)
3
3
--
--
3
6
Euglobulin lysis time (rain. < control)
0
0
12
--
24
14
31
0-10
514
700
550
700
396
560
761
200-400
1
1
3
1
5
3
0
++
++
+
Platelets 7. 10a (per c.mm.)
Fibrinogen (mg. per 100 ml.) F D P titre log 2
Spirochaete density* + + + + + ÷
0-2
0-3
0-2
++++++
*Based on the average number of spirochaetes seen in a blood fibrin per high power field; 0-1 = + , 1-3 = + + , 3 - 6 = + + + , > 6 = + + + + . Each o f the patients demonstrated a rise in serum F D P following treatment including those who were given a heparin infusion (Fig. 1). I n 3 o f the 4 control patients the increase in serum F D P was remarkable, approaching titres produced b y normal plasma in the F D P assay. A similar increase in F D P was also seen in 1 o f the 3 patients given heparin. T h e increase in F D P started within 60 minutes following administration o f tetracycline and coincided with the onset o f rigors and the disappearance o f spirochaetes from the peripheral blood. As the b o d y temperature increased abruptly, so did the F D P titre. T h e leucocyte count began to fall and the polymorphonuclear leucocytes became vacuolated; the F D P titre reached its highest level prior to the peak in b o d y temperature and the nadir o f the leucocyte count. T h e F D P titre then decreased rather quickly to near normal levels while the leucocyte count and b o d y temperature returned slowly to baseline levels (Fig. 2).
784
BLEEDING
IN LOUSE-BORNE
RELAPSING
FEVER--II.
FIBRINOLYSIS
FOLLOWING
TREATMENT
o
L~
Z
O o O L~ v "--
o ~
~o
L
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~n
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._I
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r~ I-Z
0
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8
!
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P. L. PERINE~ T. GABRE KIDAN~ D. A.'WARRELL, A. D. M. BRYCESON AND E. H. O. PARRY II
Tet rocycline
L I
785
4241-
"~
40-
~.
39-
L0~t
ta . ~,~
6I I I I I
__
~
3oo-
FIG. 2. Changes following tetracycline treatment in the first patient. The broken vertical line marks the disappearance of spirochaetes.
I
.~ 200.
~. ~ LO0-
I I I I
- -
~
5ooi
~ '- 400-~. ~.
t' 3oo-
01
I
I
I
I
I
i
2
3
4
5
Hours
In two of the control patients (Nos. 1 and 2) the increase in serum FDP was accompartied by significant decreases (P < 0-5) in the platelet count and fibrinogen concentration. In the remaining cases the platelet count did not change significantly and the fibrinogen concentration either increased or remained stable. The increase in the fibrinogen concentration coincided with the increase in FDP titre in 2 cases (Nos. 5 and 6). There were no apparent differences between the patients treated with tetracycline and heparin and those treated with tetracycline alone. Heparin did not reduce the production of FDP prior to or following tetracycline. Nor did heparin modify the other manifestations of the Herxheimer reaction. There was no significant correlation between the severity of the Herxheimer reaction and the density of the infection or the titre of FDP. No overt bleeding occurred in any patient during the time of the study. Discussion Fibrin degradation products appear in the circulation in increased amounts as a consequence of the excessive digestion of fibrinogen or fibrin by proteolytic enzymes; their presence in serum provides incontrovertible evidence for both primary and secondary
786 BLEEDING I N LOUSE-BORNE RELAPSING F E V E R ~ I I . FIBRINOLYSIS FOLLOWING TREATMENT
fibrinolysis (MERSKEYet al., 1966). The elevated FDP titres in this study could be due to in vitro fibrinolysis, as serum for FDP assay were obtained without the addition of
fibrinolytic inhibitors. However, the accelerated pretreatment euglobulin lysis times in 4 patients are evidence of increased in vivo fibrinolytic activity. The magnitude of FDP fitre elevation following treatment also favours in vivo fibrinolysis (PITNEY, 1970, personal communication) and correlates with the clinical observation of an increased bleeding tendency following the Herxheimer reaction (BRYCESONet al., 1970). The mechanisms responsible for the activation of the fibrinolytic system are unknown. It is probable that the elevated pretreatment FDP titres, the accelerated eugiobulin lysis times and the increase of FDP following treatment are partly due to the physiological stresses resulting from the infection and its treatment. The severe rigors and pyrexia which characterize the Herxheimer reaction are well recognized activators of fibrinolysis (SHERRY et al., 1959). It is also likely that the increase in FDP following treatment is caused by the disappearance of spirochaetes from the peripheral blood. Blood sampled during the fibrile reaction in LBRF has been shown to contain endotoxin presumably of spirochaetal origin (BRYCESONet al., 1970). Endotoxin effects several changes in the blood coagulation system depending upon the animal species. It rapidly stimulates new fibrinogen synthesis (LERNERet al., 1968), impairs fibrinolysis by inhibiting the release of plasminogen activator (LIPINSKI et al., 1969), and triggers intravascular coagulation by causing the release of thromboplasfic material from platelets (HJORT and RAPAPORT,1965). The latter process is characterized by the consumption of platelets and other coagulation factors with local or secondary activation of the fibrinolytic system in response to clotting (SHERRY, 1968). The effect of endotoxin on blood coagulation is also dose related; small doses induce massive intravascular coagulation, while larger doses produce shock with minimal evidence of clotting (MARGRETTENet al., 1967). The thrombocytopenia, decreased fibrinogen concentration and elevated FDP titres following treatment in 2 of our patients are observations consistent with the initiation of DIC by release of endotoxin from dying spirochaetes. The absence of consistent changes in the platelet counts and fibrinogen concentration in the remaining cases may be explained by the varying magnitude and duration of the endotoxemia. In some, the endotoxemia stimulated fibrinogen synthesis and increased fibrinogen concentration but was inadequate to initiate significant DIC and depletion of platelets. In these cases the elevated FDP fitres probably resulted primarily from increased plasminogenic activating by stress. Less likely causes would be the release of a plasminogen activator by spirochaetes or the release of protcase enzymes from the degenerating leucocytes. The latter are capable of digesting fibrin but their lytic activity is very weak (AsTRuI" et al., 1967) and would probably not produce FDP titres of the magnitude seen in LBRF. These alternate hypotheses may explain the elevated FDP titres in the patients treated with heparin, which should prevent DIC induced by endotoxin (MARGARETTEN et al., 1967). The therapeutic implications of this study with respect to bleeding are uncertain. Heparin infusions sufficient to prolong the coagulation time beyond 60 minutes did not prevent the rise in FDP following tetracycline. An antifibrinolytic agent such as epsilon aminocaproic acid (EACA) is indicated in bleeding caused exclusively by primary fibrinolysis or by activation of the fibrinolytic system secondary to DIC in a patient in whom the dotting has stopped and the fibrinolysis has persisted (McKAY, 1968). The thrombotic complications that arise from the use of EACA in DIC should limit its use to the patient with severe bleeding, thrombocytopenia and decreased fibrinogen concentrations who does not respond to heparin therapy (McKAY, 1968). As none of our patients had severe bleeding, we would have hesitated to use EACA had it been available.
P. L. PERINE, T. GABRE KIDAN~ D. A. WARRELL, A. D. M. BRYCESONAND E. H. O. PARRY 787
Summary Treatment of louse-borne relapsing fever was followed by a sudden increase in fibrin degradation productions (FDP) in 6 of 7 patients. The FDP were believed to be the result of fibrinolysis secondary to intravascular clotting in 2 patients who also had transient decreases in plasma fibrinogen concentration and platelet count. In the remaining cases, a mixed form of fibrinolysis with elevated circulating fibrinolytic activity and local lysis secondary to intravascular clotting was presumed to be responsible for the elevated FDP. A heparin infusion in 3 patients did not prevent the increase in FDP following treatment. REFERENCES ASTRtrP, T., HENRmrISEN,J. & KW~N, H. C. (1967). Blood, 29, 134. BRYCESON, A. D. M., PARRY, E. H. O., PERINE, P. L., ~TARRELL,D. A., VUKOTICH,D. & LEITHEAD,C. S. (1970). Quart. ft. Med., 39, 129. HJORT, P. F. & RAPAPORT, S. I. (1965). Ann. rev. Med., 16, 135. LERNER, R. G., RAPAPORT, S. I., SIEMSEN, J. K. & SPITZER, J. M. (1968). Am. J. Physiol., 214, 532. LmINSKI, B., WOROWSKI, K., JELJASZEWmZ,J., NmWmROWSKI, S. & REJNI~, L. (1969). Thrornb. Diath. haemorrh., 20, 285. MARGARETrEN,W., MCKAY, D. G. & PHILLmS,L. L. (1967). Am. J. Path., 51, 61. McKAY, D. G. (1968). Proc. R. Soc. Med., 61, 40. MERSKEY, C., KLF.INER,G. J. & JOHNSON, A. J. (1966). Blood, 28, 1. --, LALEZARI,P. & JOHNSON, A. J. (1969). Proc. Soc. exp. Biol. Med., 131, 871. PERINE, P. L., PARRY, E. H. O., VUKOTICH,D., WARRELL, D. A. & BRYCESON,A. D. M. (1971) Trans. R. Soc. trop. Med. Hyg., 65, 776. RATNOFF, O. D. & MENZm, C. (1951). ft. Lab. din. Med., 37, 316. SCHOFIELD, T. P. C., TALBOT, J. M., BRYCESON, A. D. M. & PARRY, E. H. O. (1968). Lancet, 1, 58. SHERRY, S. (1968). Ann. rev. Med., 19, 247. --, LINDEMEYER,R. I., FLETCHER,A. P. & ALKJAERSlG,N. (1959). ft. din. Invest., 38, 810. VON KAULLA, K. N. & SCHULTZ, R. L. (1958). Am. J. din, Path., 29, 104. ~¢'ARRELL, D. A., POPE, H. M., PARRY, E. H. O., PERINE, P. L. & BRYCESON,A. D. M. (1970). Clin. Sci., 39, 123.